Summary of Work: Neutrophils have been considered to be end- differentiated cells that have little or no ability to modulate the inflammatory responses of other cells. More recently, it has become clear that neutrophils release certain cytokines and that altering neutrophil function or number has profound effects on the systemic inflammatory response induced by endotoxin or sepsis. The mechanisms by which neutrophils modulate inflammatory responses are not well defined but appear to be mediated by more than simple antibacterial or antitoxin effects. Our work explores the mechanisms by which neutrophils affect monocyte/macrophage and endothelial cell function. Further, we are collaborating with Dr. Malech (MAID) to examine these effects in patients with chronic granulomatous disease and in volunteers given granulocyte colony stimulating factor (G-CSF). We have found that production of pro-inflammatory cytokines is downregulated and production of anti-inflammatory cytokines is upregulated in monocytes co-cultured with human neutrophils via a mechanism that requires direct cell-to-cell contact (Abstract, AFCR, 1996). Ex vivo studies using a whole blood TNF assay in G-CSF-stimulated normal volunteers shows that neutrophil number and state of activation has profound effects on cytokine production (Abstract, American Thoracic Society, 1996). Current work is focusing on the cell surface molecules involved in these responses. Regulation of the inflammatory response by neutrophils may be an important mechanism that represents a potential new therapeutic target for treating sepsis.